Novel salt of 4-({(4s)-1-(4-carbamimidoylbenzoyl)-4-[4(methylsulfonyl)piperazin-1-yl]-l-prolyl}amino) benzoic acid and novel crystal form thereof

Abstract

4-({(4S)-1-(4-Carbamimidoylbenzoyl)-4-[4-(methylsulfonyl)piperazin-1-yl]-L-prolyl}amino) benzoic acid di(4-toluenesulfonate) or dibenzenesulfonate or their crystal forms can be useful pharmaceutical ingredients because of their low hygroscopicity and excellent storage stability.

1 . 4-({(4S)-1-(4-Carbamimidoylbenzoyl)-4-[4-(methylsulfonyl)piperazin-1-yl]-L-prolyl}amino) benzoic acid di(4-toluenesulfonate). 
     
     
         2 . The 4-({(4S)-1-(4-Carbamimidoylbenzoyl)-4-[4-(methylsulfonyl)piperazin-1-yl]-L-prolyl}amino) benzoic acid di(4-toluenesulfonate) according to  claim 1 , which is in a crystal form. 
     
     
         3 . The crystal according to  claim 2 , having, in a powder X-ray diffraction spectrum, at least two or more diffraction peaks at diffraction angles (2θ) selected from about 6.2, about 7.8, about 9.4, about 11.7, about 15.6, about 16.0, about 16.3, about 17.1, about 18.6, about 20.0, about 20.3, about 21.3, about 22.4, about 23.0, about 23.5, about 23.8, about 24.1, about 24.7, about 25.9, and about 27.2 degrees. 
     
     
         4 . The crystal according to  claim 2 , having, in a powder X-ray diffraction spectrum, diffraction peaks at diffraction angles (2θ) of about 6.2, about 7.8, about 9.4, about 11.7, about 15.6, about 16.0, about 16.3, about 17.1, about 18.6, about 20.0, about 20.3, about 21.3, about 22.4, about 23.0, about 23.5, about 23.8, about 24.1, about 24.7, about 25.9, and about 27.2 degrees. 
     
     
         5 . The crystal according to  claim 2 , characterized by a powder X-ray diffraction spectrum chart shown in  FIG. 1 . 
     
     
         6 . The crystal according to  claim 2 , having an onset temperature of about 216° C. or an endothermic peak temperature of about 228° C. in differential scanning calorimetry. 
     
     
         7 . The crystal according to  claim 6 , characterized by a differential scanning calorimetry chart shown in  FIG. 5 . 
     
     
         8 .  4 -({(4S)-1-(4-Carbamimidoylbenzoyl)-4-[4-(methylsulfonyl)piperazin-1-yl]-L-prolyl}amino) benzoic acid dibenzenesulfonate. 
     
     
         9 . The 4-({(4S)-1-(4-Carbamimidoylbenzoyl)-4-[4-(methylsulfonyl)piperazin-1-yl]-L-prolyl}amino) benzoic acid dibenzenesulfonate according to  claim 8 , which is in a crystal form. 
     
     
         10 . The crystal according to  claim 9 , having, in a powder X-ray diffraction spectrum, at least two or more diffraction peaks at diffraction angles (2θ) selected from about 6.2, about 7.7, about 12.0, about 12.5, about 16.2, about 17.2, about 17.7, about 18.6, about 18.8, about 19.0, about 20.3, about 20.8, about 21.5, about 22.5, about 22.9, and about 23.1 degrees. 
     
     
         11 . The crystal according to  claim 9 , having, in a powder X-ray diffraction spectrum, diffraction peaks at diffraction angles (2θ) of about 6.2, about 7.7, about 12.0, about 12.5, about 16.2, about 17.2, about 17.7, about 18.6, about 18.8, about 19.0, about 20.3, about 20.8, about 21.5, about 22.5, about 22.9, and about 23.1 degrees. 
     
     
         12 . The crystal according to  claim 9 , characterized by a powder X-ray diffraction spectrum chart shown in  FIG. 2 . 
     
     
         13 . The crystal according to  claim 9 , having an onset temperature of about 203° C. or an endothermic peak temperature of about 213° C. in differential scanning calorimetry. 
     
     
         14 . The crystal according to  claim 13 , characterized by a differential scanning calorimetry chart shown in  FIG. 6 . 
     
     
         15 . A pharmaceutical composition comprising 4-({(4S)-1-(4-carbamimidoylbenzoyl)-4-[4-(methylsulfonyl)piperazin-1-yl]-L-prolyl}amino) benzoic acid di(4-toluenesulfonate) according to  claim 1 . 
     
     
         16 . A pharmaceutical composition comprising 4-({(4S)-1-(4-carbamimidoylbenzoyl)-4-[4-(methylsulfonyl)piperazin-1-yl]-L-prolyl}amino) benzoic acid dibenzenesulfonate according to  claim 8 . 
     
     
         17 . The pharmaceutical composition according to  claim 15 , which is a blood coagulation factor XIa inhibitor. 
     
     
         18 . The pharmaceutical composition according to  claim 15 , which is a drug for preventing and/or treating blood coagulation factor XIa-related disease. 
     
     
         19 . The pharmaceutical composition according to  claim 18 , wherein the blood coagulation factor XIa-related disease is thromboembolic disease. 
     
     
         20 . The pharmaceutical composition according to  claim 19 , wherein the thromboembolic disease is acute coronary syndrome, disseminated intravascular coagulation (DIC) or cerebral infarction. 
     
     
         21 . The pharmaceutical composition according to  claim 16 , which is a blood coagulation factor XIa inhibitor. 
     
     
         22 . The pharmaceutical composition according to  claim 16 , which is a drug for preventing and/or treating blood coagulation factor XIa-related disease. 
     
     
         23 . The pharmaceutical composition according to  claim 22 , wherein the blood coagulation factor XIa-related disease is thromboembolic disease. 
     
     
         24 . The pharmaceutical composition according to  claim 23 , wherein the thromboembolic disease is acute coronary syndrome, disseminated intravascular coagulation (DIC) or cerebral infarction.